A growing body of evidence indicates the importance of cell adhesion molecules in regulating synapse formation, stability and function in the central nervous system (CNS). T-cadherin encoded by the Cdh13 gene, is a unique GPI-linked cadherin type adhesion protein discovered and extensively studied in our laboratory. Our work in the cardiovascular system established T- cadherin as a physiological key receptor/co-receptor for APN functions (Hebbard et al. 2008;Denzel et al 2010). Mutations in the human CDH13 gene have been associated with hypoadiponectemia and cardiovascular dysfunctions. In the nervous system, human case- control studies have linked clusters of nearby CDH13 SNPs to attention deficit hyperactivity and comorbid neuropsychiatric disorders. Elucidating functions for T-cadherin in the nervous system in Cdh13-deficient mice, we discovered defects in hippocampal synaptic function and plasticity manifesting in dendritic spine changes of Cdh13-deficient principal neurons. T-cadherin is expressed by GABAergic interneurons synapsing on dendrites of the principal pyramidal neurons that do not express T-cadherin. A major discovery that could bear on this issue is the fact that Adiponectin (APN), genetically requiring T-cadherin for regulating functions in the periphery, is expressed by hippocampal pyramidal cell receiving inputs from T-cadherin- expressing interneurons. In combination, these findings raise the intriguing hypothesis that APN is part of the T-cadherin signaling pathway that modulates circuits in the hippocampus, with profound affects on associative memory behaviors as Cdh13-KO mice show significant impairments in fear- and reward-based conditioning tests. In this exploratory proposal, we will genetically test the role of APN in hippocampal synaptic functions in relation to T-cadherin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH103861-01
Application #
8685062
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Desmond, Nancy L
Project Start
2014-04-03
Project End
2016-03-31
Budget Start
2014-04-03
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$292,500
Indirect Cost
$142,500
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037